| Method of preparing 4-r-substituted 4-demethoxydaunorubicin -> Monitor Keywords |
|
|
  Method of preparing 4-r-substituted 4-demethoxydaunorubicinRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, , Oxygen Of The Saccharide Radical Bonded Directly To A Polycyclo Ring System Of Three Or More Carbocyclic Rings, Oxygen Of The Saccharide Radical Bonded Directly To A Polycyclo Ring System Of Four Carbocyclic Rings (e.g., Daunomycin, Etc.)The Patent Description & Claims data below is from USPTO Patent Application 20060205684. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional Application No. 60/472,192 filed on May 21, 2003. U.S. provisional Application No. 60/472,192 is incorporated by reference as if set forth fully herein. FIELD OF THE INVENTION [0002] The field of the invention generally relates to chemical methods used to produce anthracyclines. More specifically, the field of the invention relates to methods and processes used to produce 4-R-substituted 4-demethoxydaunorubicin having the formula (I) described more fully herein from 4-demethyldaunorubicin. In the case where R.dbd.H, the present invention relates to chemical methods and processes used to produce idarubicin from 4-demethyldaunorubicin. BACKGROUND OF THE INVENTION [0003] Anthracyclines form one of the largest families of naturally occurring bioactive compounds. Several members of this family have shown to be clinically effective anti-neoplastic agents. These include, for example, daunorubicin, doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, aclarubicin, and carminomycin. For instance, these compounds have shown to be useful in bone marrow transplants, stem cell transplantation, treatment of breast carcinoma, acute lymphocytic and non-lymphocytic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, and other solid cancerous tumors. [0004] Currently known methods used to prepare 4-demethoxy-4-R-daunorubicin-type anthracyclines (where R.dbd.H the anthracycline is known as idarubicin) are based on coupling of the aglycone (synthesized by any of the known methods) and protected and activated daunosamine in the presence of silver triflate (AgOSO.sub.2CF.sub.3), trimethylsilyltriflate ((CH.sub.3).sub.3SiOSO.sub.2CF.sub.3), or a mercuric oxide-mercuric bromide system (HgO--HgBr.sub.2). For example, it is currently known to synthesize aglycone using either anthracenetetrone or isobenzofurane as the starting substance. Unfortunately, these methods of aglycone synthesis are complicated by the creation of optically active centers at carbons C7 and C9. [0005] An alternative method of synthesis of 4-demethoxydaunorubicin (idarubicin) utilizes daunorubicin aglycone which is prepared by the acidic hydrolysis of daunorubicin starting material. In this method, at the same time daunosamine is synthesized, with chemical modification, the daunosamine can be further used for glycosylation of the modified aglycone. Earlier methods involved the substitution of 4-MeO aglycone substituent for hydrogen, NH.sub.2, or other chemical groups involved demethylation of daunorubicinone, sulfonation of the resulting 4-demethoxydaunorubicinone and substitution of the 4-ArSO.sub.2O radical for a 4-ArCH.sub.2NH with further reduction of the benzyl radical leading to formation of 4-NH.sub.2.sup.- radical. See U.S. Pat. No. 4,085,548 entitled 4-DEMETHOXY-4-AMINO-ANTHRACYCLINES, issued Jan. 15, 1991, to Caruso et al., the disclosure of which is incorporated by reference as if set forth fully herein. Further reductive deamination results in production of 4-demethoxydaunorubicin (idarubicin). See EP Application No. 0328399, published Aug. 16, 1989, the disclosure of which is incorporated by reference as if set forth fully herein. [0006] There also has been described a reductive cross-condensation reaction of 4-demethyl-4-Tf-daunorubicinone on the phosphorous hydride-Pd.sub.0 catalyzing complexes. See U.S. Pat. No. 5,587,495. In these reactions, 4-R substituted daunorubicinones are produced wherein R.dbd. [0007] Similarly, reductive carbonylation of 4-Tf-daunorubicinone on the same catalysts described above results in 4-COOR substituted daunorubicinones. See U.S. Pat. No. 5,218,130. When formate is utilized as a ligand, substitution of 4-O-Tf radical for hydrogen takes place resulting in formation of 4-demethoxydaunorubicinone. See U.S. Pat. No. 5,103,029. SUMMARY OF THE INVENTION [0008] The present invention relates to processes used to prepare 4-R-substituted anthracyclines and their corresponding salts of formula (I) shown below from 4-demethyldaunorubicin: Wherein R is defined as hydrogen, a linear or branched oxy[alkyl, alkenyl or alkynyl] group comprised of one to sixteen carbon atoms, or a complex ester group COOR.sub.1', wherein R.sub.1' is a linear or branched alkyl, alkenyl or alkyne group of up to ten carbon atoms, comprising the steps of: [0009] (1) providing 4-demethyldaunorubicin or a derivative of 4-demethyldaunorubicin of formula (II) wherein R.sub.1 comprises H, acyl or acyl halide and R.sub.2 comprises H, acyl or acyl halide, carbonate, or Schiff's base [0010] (2) treating the 4-demethyldaunorubicin or the derivative of 4-demethyldaunorubicin of formula (II) with a sulfonylating agent having a chemical formula R.sub.3--SO.sub.2--X, wherein R.sub.3 is an alkyl group, an alkyl halide group or an aryl group, X is a halide group or --O--SO.sub.2--R.sub.3 to form 4-demethyl-4-sulfonyl-daunorubicin having formula (III) wherein R.sub.3 comprises an alkyl group having from 1 to 4 carbon atoms optionally substituted by one or more halogen atoms or an aryl group optionally substituted by halogen, alkyl, aloxy or nitro, R.sub.1 comprises hydrogen, acyl, or acyl halide, and R.sub.2 comprises hydrogen, acyl, acyl halide, carbonate, or Schiff's base; [0011] (3) reacting the 4-demethyl-4-sulfonyl-daunorubicin of formula (III) with a reducing agent in the presence of catalytic quantities of a compound having formula (IV) ML.sub.pL'.sub.q (IV) wherein M represent a transition metal atom; L and L', wherein L and L' represent the same or different anions or a neutral molecule, and p and q may vary from zero to four, to produce protected 4-demethoxydaunomycin having a formula (V), [0012] (4) hydrolyzing the protected 4-demethoxydaunomycin in a basic solution to produce a 4-R-substituted anthracycline of formula (I). [0013] The present invention uses a novel method of synthesis which lacks the step of forming a stereospecific glycoside bond between aglycone and aminoglycoside. The inventors have found that the novel method of synthesis increases the yield of the final product to up to 30-40% from (II). It thus is an object of the invention to provide a method of synthesis which reduces the number of steps involved to produce 4-R-substituted 4-demethoxydaunorubicin. It is a further object of the invention to provide a method of synthesis which increases the yield of the process. DETAILED DESCRIPTION OF THE INVENTION [0014] The present invention is directed to methods used to prepare 4-R-substituted anthracyclines and their corresponding salts of formula (I) shown below [0015] Formula (I) illustrates a salt of a 4-R-substituted anthracyclines. It should be understood, however, that the present method contemplates the synthesis of 4-R-substituted anthracyclines of formula (I) in both the salt and non-salt forms. With respect to the salt form shown in Formula (I), An.sup.- is preferably a anion of a strong acid, for example, hydrochloric or hydrobromic acid. In Formula (I), R may comprise hydrogen (for example, in the case of idarubicin), a linear or branched oxy[alkyl, alkenyl, or alkynyl] group comprised of between one to sixteen carbon atoms. In the case of a linear or branched oxy [alkyl, alkenyl, or alkynyl] group, R preferably has less than or equal to four carbon atoms. [0016] The linear or branched oxy[alkyl, alkenyl, or alkynyl] group may be partially substituted for an aryl group (both unsubstituted and substituted) for any inert group such as, for example, an alkyl group, an alkoxy group, or a nitro group. In addition, the linear or branched oxy group may be partially substituted for an alkoxy group, a trialkylsilyl group, ester group, or amide group. [0017] R may also comprise a complex ester group, COOR.sub.1', where R.sub.1' is a linear or branched alkyl, alkenyl or alkyne group of up to ten carbon atoms. [0018] The synthesis of the 4-R-substituted anthracycline of formula (I) begins by providing a starting compound, preferably 4-demethyldaunorubicin or a derivative of 4-demethyldaunorubicin of formula (II) wherein R.sub.1 comprises H, acyl or acyl halide and R.sub.2 comprises H, acyl or acyl halide, carbonate, or Schiff's base; (preferably COCF.sub.3). [0019] Next, the compound of formula (II) is treated with a sufonylating agent having the chemical formula R.sub.3--SO.sub.2--X, where R.sub.3 comprises an alkyl group, alkyl halide group or an aryl group and X comprises a halide or --O--SO.sub.2--R.sub.3. The reaction is preferably conducted in pyridine in the presence of sterically hindered tertiary amine, for example, N,N-diisoprolylethylamine, and catalytic quantities of N,N-dimethylaminopyridine. The reaction involves mostly C4-OH. In addition, hydroxyl groups at C6, C11 and C9 react principally in special conditions allowing utilization of unprotected derivatives of the 4-demethyldaunorubicin at these carbon positions. The above steps produce 4-demethyl-4-sulfonyl-daunorubicin having formula (III) wherein R.sub.3 comprises an alkyl group having one to four carbon atoms optionally substituted by one or more halogen atoms or an aryl group optionally substituted by a halogen group, alkyl group, aloxy group, or nitro group. Preferred groups for R.sub.3 include trifluoromethyl, 4-fluorophenyl, and 4-tolyl. R.sub.1 preferably comprises hydrogen, acyl, or acyl halide. R.sub.2 preferably comprises hydrogen, acyl, acyl halide, carbonate, or Schiff's base (i.e., a compound formed by a condensation reaction between an aromatic amine and an aldehyde or ketone). Continue reading... Full patent description for Method of preparing 4-r-substituted 4-demethoxydaunorubicin Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method of preparing 4-r-substituted 4-demethoxydaunorubicin patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. Start now! - Receive info on patent apps like Method of preparing 4-r-substituted 4-demethoxydaunorubicin or other areas of interest. ### Previous Patent Application: Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same Next Patent Application: Azacytosine analogs and derivatives Industry Class: Drug, bio-affecting and body treating compositions ### FreshPatents.com Support Thank you for viewing the Method of preparing 4-r-substituted 4-demethoxydaunorubicin patent info. IP-related news and info Results in 0.3633 seconds Other interesting Feshpatents.com categories: Tyco , Unilever , Warner-lambert , 3m |
||
